Phenylketonuria: Mental development, behavior, and termination of low phenylalanine diet

646

May, 1968 T h e Journal of P E D I A T R I C S

Pbenylketonuria: Mental development, behavior, and termination of lowphenylalanine diet Psychological and biochemical data on 46 children with phenylketonuria followed at The Hospital for Sick Children, Toronto, for 7~., )'ears are reported. In cases diagnosed and treated before the age of two years the eventual level of intelligence was above mental deficiency. When the I.Q. was within normal limits there were invariably mental handicaps resulting in poorer school progress than anticipated. Significance of the high incidence of autistic behavior in the group is discussed. Fourteen children arbitrarily removed from diet were studied [or periods o[ 18 to 48 months.

I. M. Hackney, Ph.D., W. B. Hanley, M.D.,* W. Davidson, M.B., Ch.B., and L. Lindsao, M.D. TORONTO~

C o N C E R N

ONTARIO~

t{ A S

CANADA

B E E N

expressed r e -

lack of knowledge and lack of investigation into the relationship between behavior defects and biochemical defects in phenylketonuria, z-:~ In Part I a summary is presented of psychologicaI and biochemical data from 46 cases of phenylketonuria in the untreated and treated state, all diagnosed prior to mass

garding

From the Departments of Psychology and Pediatrics, The Hospital for Sick Children, and the University of Toronto, Toronto, Ont., Canada. ~Address: The Hospital tot Sick Children, 555 University Avenue, Toronto 5, Ont., Canada.

Vol. 72, No. 5, pp. 646-655

screening of newborn infants in our area. "They include all patients seen at a special clinic at The Hospital for Sick Children, Toronto, over a 7 ~ year period ending June, 1966 (see Table I ) . In Part I I we have discontinued low phenylalanine dietary treatment in 14 cases. Follow-up of these cases to June, 1967, is reported, at which time the patients have been '"off diet" for from 18 months to four years (see Table I V ) . The emphasis in this report is upon an examination of mental development and behavioral anomalies in relation to biochemical data.

Volume 72 Number 5

P A R T I. M E N T A L D E V E L O P M E N T

Phenylketonuria

64 7

AND BEHAVIOR

M A T E R I A L AND M E T H O D S

Cases. All cases attending the clinic during the 7y~ year period have been included (44 children, plus one adolescent and one adult). Method of diagnosis is shown in Table I. Some of these cases have been reported previously.4, 5 Clinical management. We originally used the method of Udenfriend and Cooper G,7 for determining serum phenylalanine levels, but latterly we used the fluorometric method of McCaman and Robins. s Attempts were made by dietary management to keep the fasting serum phenylalanine values within normal limits (1 to 3 mg. per cent). Patients were seen once a week in the early stages of therapy. The period was gradually extended to every two or three months for the older children, depending on ease of controlling the serum phenylalanine levels. A pediatrician made the clinical assessments, and biochemical studies were carried out at each visit. Psychological examinations. Intelligence. The same psychologist (I. M. H.) tested the patients repeatedly, using the Cattell, the Stanford-Binet, and the Wechsler scales. The children's handicaps frequently prevented completion of tests. When intelligence quotients were obtained, they are reported in numbers, and when there is an estimate only, it is reported in approximate terms. We also collected data on mental handicaps, particularly those related to organic factors in mental functioning. Mental handicaps. Neuropsychological handicaps, short attention span, distractibility, hyperactivity, low frustration tolerance, unreliable memory, poor space perception and perceptual organization, concrete and rigid reasoning, perseveration, slow language development with articulation defects, echolalia and dysphasia, poor motor coordination, variability in learning and retention from hour to hour and day to day were recorded.

Behavior anomalies. Autistic behavior patterns of repetitive bizarre movements and stylized posturing, and symptoms of chronic anxiety were noted. RESULTS

Untreated state--22 cases. Twenty children, one adolescent, and one adult, ranging in age from four months to 36 years, had psychological examinations at the time of diagnosis. Intelligence. The standard statistical classification of levels of intelligence was used (Table I I ) . Mental handicaps. Not one was found to be entirely normal in mental functioning. All were severely handicapped in learning, either because of mental deficiency or neuropsychological handicaps or both. It should be noted that this group includes few infants (see (Table I). Behavior anomalies. Sixteen of the 22 patients were observed by the clinic team to have behavior anomalies. Seven who were infants were extremely inactive, vague, and unresponsive. Of the nine older children, four showed autistic behavior patterns, and five were remarkably vague or irritable. Treated state---44 eases. This group includes the 20 children assessed in the untreated state. Intelligence. Levels at the last assessment while on dietary treatment are shown in Table III. Of the 13 children whose treatment was begun in the first two months of life, 12 now have intelligence quotients above 70 (above mental deficiency). They account for 54 per cent of the 22 children whose rating is above mental deficiency. However, their mental functioning is not normal. All are mentally handicapped, including those whose intelligence quotients fall in the average range statistically. Exhaustive examination of our records has led to the conclusion that genuine increment

648

Hackney et al,

The ]ournal o[ Pediatrics May 1968

T a b l e I. P s y c h o l o g i c a l a n d b i o c h e m i c a l d a t a o n 46 p h e n y l k e t o n u r i c c h i l d r e n ' a n d o n e a d u l t

Patient No.

Age (yr.--moO

1

0--7

~2 82

I--1

Age (yr.--too 0 First psych. Last psych.

Initial 1.(2. level~

Serum phenylalanine level (mg./lO0 ml.)

40-60

--

S

0--7

7--11

37.93

C

1--2

4--10

41.67

S

0--4

5--3

35.5

MR

1--0

5--11

33.0

R

1--6

2--6

~40

13

16 da.

4

0--11

5

0--2

6

5 da.

7

1--1

50-70

8

2--3

60-70

9

4 da.

10

0--11

11

60-75

68.0

Ho[o

diagnosed*

assess,

assess.

S

0--7

I--6

MR

1--1

6--2

24.56

S

2--3

7--5

14.4

S

0--9

2--7

32.6

MR

0--11

7--0

7--0

26.01

MR

7--10

8--4

12

5 da.

68.0

S

0--8

1--6

13

0--7

39.6

C

1--0

3--0

14

0--2

79,0

R

1--4

2--4

15

3--0

--

MR

6--2

7--1

16

1--7

54.0

MR

1--7

4--5

17

2--11

32.7

MR

3--2

9--4

18

0--1

49.0

S

1--2

4--6

19

0--4

~ 20.0

S

0--4

4--10

50-65

~ 40

50-60

~ 30.0

20

36

102

20.8

PKU

21

13--0

35

37.0

MR

22

1--3

50-60

34.8

MR

1--3

7--1

23

I--3

50-70

68.5

MR

1--3

2--3

24

0--2

49.1

S

0--10

7--10

25

0--11

~ 60

26.71

S

0--11

6--1

26

0--3

? in 80's

30.0

S

0--4

5--0

27

0-- 7

40-50

30.0

MR

0--7

2 - - 10

28

2--0

18.0

MR

2--2

6--4

29

11 da.

40.0

S

2--0

30

0--2

63.5

R

3--0

*How diagnosed: S. sib known P K U ; B, behavior problem; R, routine screening (urine); MR, mental retardation; C, convulsions ?Rating of intelligence assessment: S, satisfactory assessment on at least one occasion with I.O. judged to be a valid e s t i m a t e , ~- ~Overtreatment: Over one third phenyl readings less than 1.5 rag. per cent in first six months of life; X, overtreated; O, nc w control: Good, 80 per cent of readings of serum phenylalanine level below 9 mg. per 100 ml.; fair, 60 per cent f level below 9 mg. per 100 ml. [IHandicaps: A, autistic behavior patterns; NH, neuropsychological handicaps; E, emotional or behavioral problem, unaccompanie, 82

of same family arc bracketed,

Volume

Phenylketonuria

72

Number 5

Later 1.(2. level

Intelligence I Intellectual ratingt change on diet

Overtreatment~

Dietary controlw In first After 2 years age 2

Handicapsll

36

S

Decrement

Good

Poor

NH

40

U

Decrement

Poor

Poor

NH

86

U

No change

Poor

Poor

NH

70-80

U

No change

Good

Poor

NH

H i g h 80's

U

No change

+

Poor

Poor

E

Low 90's

U

No change

0

Good

--

67

S

No change

Good

Good

E

86

S

Increment

--

Poor

E

U

No change

Good

Poor

60-80

U

?Increment

Good

Poor

NH

55

S

No change

--

Poor

NH

H i g h 70's

U

No change

I n 50's

U

No change

I n 70's

U

No change

34

S

?Increment

In 60's

U

?Increment

85-95

U

?Increment

97

S

?Increment

I n 60's

U

?Increment

H i g h 80's

+

+

+

Good

Poor

Good

Fair

NH

Good

Good

NH

--

Good

NH

Good

Poor

NH

--

Poor

NH

+

Good

Poor

NH

+

Good

Good

NH

0

649

NH NH 37

S

Decrement

--

Poor

In 70's

U

?Increment

Good

Good

A

83

S

No change

Good

Poor

NH

60-70

U

?No change

Good

Poor

NH

65

S

?No change

Fair

Poor

In 40's

U

No change

Good

Poor

25

U

No change

--

Poor

98

S

84

S

Moved to Chicago

+

+

A NH

E, eczema. Note. These diagnoses were m a d e before routine Guthrie screening tests were instituted in the newborn mtrseries in Ontario. child's intelligence; U, unsatisfactory assessment; stated I. Q. based on "best estimate" from a number of attempts at formal assessment. overtreated. readings of serum phenylalanlne by neuropsychological

handicap

level below 9 mg. per 100 ml.; pore', less than 60 per cent of readings of s m u m phenylalanine or autistic behavior patterns.

Continued

650

H a e k m 3, el a[.

The Journal o/ Pediatrics May 1968

T a b l e I. C o n t ' d i

Patient No.

,4 ge

O,r.--mo.)

31

0

9

32

0

fl

33

I

9

34

2

!)

35

t)

5

Initial I.@ level

Serum phenylalanine level (mg./lO0 ml.)

< 40

Age (yr.--too.) How

First psych.

dia enosede

assess,

Last psych. i

assess.

36.0

MR

0--9

2-- 7

40-50

43.0

MR

0--9

I -9

40

22.7

MR

1 9

8

24.o

MR

2

2- 7

5I)

2

11

38.0

E

0

5

4- 6

51.0

R

2

8

3

7

36.!1

S

I

I0

2

11

8

2- 6

)

[37

5 (la.

38

19 8

50

24.(~

MR

i

39

I1. 9

< 4-0

21.9

E

0--1t)

90

25.0

B

4{/

11

41

I I da.

5

1 I--5

6

5

11- 10

71.0

S

1

2

I

11

42

7 . G~

19.5

R

7--5

8

5

43

~

9

21.2

C

1 o

t

1

44

1 9

19.3

C

2

10

6

1l

[ 45

1.-- '.~

42.0

C

i-- I(}

2

ll

1.- 8

38.6

S

I

2

1t

/

[ 46

in intelligence while on diet has not occurred. F o u r children deteriorated while on diet, two of these in association with m a j o r convulsive episodes, a n d one with progressively severe autistic behavior patterns. We noted repeatedly that small rises and falls in intelligence quotient coincided with rises and falls in parental hope. M e n t a l handicaps. T w e n t y - t w o (50 per cent) showed neuropsychological handicaps, i m p o r t a n t barriers to progress in school. I n fact, all who are of school age are making poorer progress than would be predicted from intelligence quotient a]one. Behavior anomalies. Nine (20.5 per cent) showed autistic behavior patterns, remarkably numerous for such a rare disorder, and w a r r a n t i n g further study. These children over the first years tended to lose their bizarre behavior patterns and now behave like "ordinary" m e n t a l defectives.:' Four children had emotional a n d be-

lO

havioral disorders. O n e was schizoid, and the other three had anxiety reactions. I n the r e m a i n i n g nine cases who had no special m e n t a l or behavior problems, eight are pre-schoolers, and our experience leads us to caution in predicting their future. Two definite findings have emerged from a n analysis of our cases: (1) W h e n the diagnosis was made a n d the child treated before age two months, the eventual level of intelligence was above the level of mental deficiency. (2) Even when the measured intelligence quotient was within normal limits, there were invariably m e n t a l handicaps which result in poorer school progress t h a n would be predicted from the intelligence quotient alone. DISCUSSION

P h e n y l a l a n i n e levels. T h e relationships between initial diagnostic serum p h e n y l a l a n i n e levels a n d u l t i m a t e intelligence and behavior"

Volume 72 Number 5

Phenylketonuria

65 1

Dietary controlw Later I.(2. level

Intelligence ratingt

Overtreatment~.

Intellectual

change on diet

In first 2 years

Alter age 2

Handicapsll

Poor

A

Fair

A

40

U

Decrement

Good

In 70's

U

Increment

Poor

50

S

No change

In 70's

U

?Increment

--

Fair

A

50

U

No change

Fair

Poor

E

-

-

72

S

No change

Fair

Poor

NH

In 60's

U

No change

Good

Good

A

In 40's

U

No change

Good

Good

A

40

U

No change

Fair

Poor

A

83

S

No change

--

Poor

NH

U

No change

Poor

56

S

No change

60

U

Increment

Good

Fair

A

53

S

Increment

--

Poor

NH

30

U

No change

Good

Good

NH

In 70's

U

?Increment

Good

Poor

NH

High 70's

NH

Table I I I

Table II

Intelligence level I.Q. Mental deficiency < 70 Borderline 70-79 Dull normal to average ) 80 Total

No. of Per cent patients of total 17 77.3 2 9.1 3 22

13.6 100

were variable. Review of our cases in the treated a n d u n t r e a t e d state, however, brought forth the following observations. I n 13 cases with relatively low diagnostic serum p h e n y l a l a n i n e levels (below 25 mg. per c e n t ) , two who were diagnosed in late childhood a n d adulthood had intelligence quotients of 91 a n d 102, respectively. Two-thirds of our cases of autistic behavior patterns also fall in this group. T h o u g h the majority of published reports on u n t r e a t e d phenylketo-

Intelligence level I.Q, Mental deficiency ~ 70 Borderline 70-79 Dull normal to average ) 80 Total

No. of Per cent patients of total 22 50.0 10 22.7 12 44

27.3 100

nuric children with high intelligence quotients reveal relatively low serum phenylalanine levels,3, 10-14 the coincidence of these low levels with autistic behavior patterns has not been reported before a n d c a n n o t be interpreted in the light of present knowledge. I n ten patients with relatively high (over 49 rag. per cent) initial serum p h e n y l a l a n i n e levels, most did not have initial intelligence tests performed because of their young age, b u t later tests showed nine of the ten to have

65 2

Hackney c t a l .

intelligence quotients above 70. However, since the disease in eight of the ten was diagnosed and treated before two months of age, we cannot necessarily conclude that high diagnostic serum phenylalanine levels mean more severe potential brain damage. The high serum phenylalanine levels in the younger patients probably reflect the relatively greater protein intake at this age, as well as a degree of renal and metabolic immaturity. The question remains unanswered whether there may be a relationship between initial diagnostic serum phenylalanine level and level of intelligence. Adequacy of biochemical control. This is a continually perplexing factor. In our cases, the children tend to be in "good" dietary control until age two years, and then go out of control. Of five families with two or more phenylketonuric children, in four the dullest child maintained best biochemical control after age two years. Role of "overtreatment." We continue to be doubtful whether or not the mental impairment can be attributed entirely to the effect of elevated serum phenylalanine. Recently evidence has appeared that undernutrition in early life may produce subnormal mental development ~:'-'s Using our own criterion for overtreatment, i.e., one third of the readings of serum phenylalanine levels below 1.5 rag. per cent in the first six months, we find that, of 14 babies treated during the first six months, 12 were "overtreated." Weight gain and linear growth were unsatisfactory. All were below the 10th percentile for weight and height. Though we suspect it is a factor, no clear relationship can be demonstrated between "overtreat-

The ]ournal o[ Pediatrics May 1968

ment" and the mental impairments which these children now show? 9 In general the experience with our patients has led to a cautious prognosis in all respects. It also points up the stress on parent and child, especially when the child's intelligence is close to normal limits. The parents invariably hoped their children would be normal. When the phenylketonuric child, who appeared normal in his early life, shows up in school as handicapped, the resultant pressures on parents and child are severe. The following hypotheses, worthy of further study, have suggested themselves as a result of examination of our cases. It may be : (1) that no matter how early treatment is begun, some brain damage has occurred, and the child's mental development will not be entirely normal, although the measured I.Q. may be "normal" or "average"; (2) that the diet tends to arrest the deteriorative process, but cannot improve mental development; (3) that the critical period for treatment is the first two months, and after the age of two years the diet does not benefit the child's mental development; (4) that there is something unique about the damage caused by phenylketonuria, since it is often associated with autistic behavior patterns; (5) that "good" dietary control does not always result in good mental development, especially if the child convulses; (6) that the diet does not provide adequate nutrition for the young infant to allow for normal mental development; (7) that a guarded prognosis of academic and vocational achievement is justified, even when the child's physical and mental developments are technically within normal limits.

P A R T II. T E R M I N A T I O N OF LOW P H E N Y L A L A N I N E D I E T e

The dietary treatment of phenylketonuria is onerous for both patient and parents, and because of economic and emotional hardships it is desirable to discontinue the diet as soon as it is safe to do so. ~Presented in part by W. Davidson at the joint meeting of tile Canadian and New England Paediatric Societies, Halifax, N.S., Canada, July 11, 1966,

Diet has been terminated arbitrarily at age five to eight years in 14 of our cases. These are children whose disease was diagnosed and treated late, the earliest at age seven months. Psychological and biochemical follow-ups to June, 1967, are reported, at which time diet had been discontinued between 18 and 48 months (see Table I V ) .

Volume 72 Number 5

Phenylketonuria

653

Table IV. Intellectual levels of 14 phenylketonuric children at diagnosis, on diet, and after termination of diet Off diet

During diet At diagnosis Patient Age No. (yr.--moO 1.(2. 1 0--7 40-60 3 16 days -4 0--11 60-75 7 1--1 50-70 8 2--3 60-70 10 0--11 50-65 15 3--0 -17 2--11 -22 1--3 50-60 25 0--11 ~ 60 28 0--7 -33 1--9 ~ 40 39 0--9 ~ 40 44 1--9 -~Returned to diet. See text.

Intellectual

1.(2. 36 86 70-80 67 86 60-80 34 85-95 37 60-70 ~ 25 50 ~ 40 53

change while on diet Decrement No change No change No change Increment ?Increment ?Increment ?Increment Decrement ?No change No change No change No change ?Increment

RESULTS Intelligence. N o change. Of 12 patients, seven have clearly shown no change when taken off diet. T h e remaining five children have shown great variability, especially Patient 8, whose mental functioning constantly fluctuates. These are the children with the highest intelligence quotients; all are in regular school classes, are making poor progress, and are showing anxiety reactions which interfere with mental efficiency. Intellectual increment. One child, Patient 44, showed a dramatic rise of 23 I.Q. points when taken off diet. This change is ambiguous, since the child's emotional condition had improved greatly with a change of schools. Intellectual decrement. One child, Patient 25, deteriorated when taken off diet for six months. H e r mental age on formal testing dropped by a year, and her behavior became very agitated. R e t u r n e d to diet, and retested two months later and again ten months after resuming diet, her mental age had risen. Her behavior also improved greatly, and the previous agitation and mental disorganization disappeared. T h e effect of emotional factors is unclear, since she also had changed

Most recent test

Intellectual

Age (yr.--moO 9--7 6--3 8--2 7--6 8--7 8--4 12--10 1 I--3 9--6 7--8 9--4 9--3 8--I 8--4

change since off diet No change ?No change ?No change ?No change ?No change No change No change ?No change No change ?Decrement No change No change No change Increment

I.(2. 40 93 72 66 77 80 40 96 31 63 25 52 37 76

Months

off diet 35 18 26 29 32 42 48 39 24 6; 10" 25 31 23 32

schools with benefit. We do not know how m u c h of the improvement was due to going back on diet, and how m u c h to removing unreasonable academic pressures from the child. She was taken off diet again for a period of ten months, but was restarted by the mother because of short attention span at school and increasing irritability at home. H e r intelligence quotients have remained the same, but her irritability has decreased. Behavior. M o r e than half of the parents feel the child's behavior has improved off diet, because there is no longer conflict about not being allowed the food that the rest of the family eats. T h e r e have been no instances of behavioral deterioration, except in the case of C. I. already noted. DISCUSSION Serum phenylalanine levels after termination of diet have risen to levels ranging from 16.5 to 43.0 rag. per cent. T h e r e have been no observable relationships between these levels and other factors being studied. T h e medical literature contains widely divergent opinions as to the advisability of discontinuing the low phenylalanine diet in phenylketonuria. Some authors are in favor of early termination of diet, 2~176while others

65 4

Hack~zey ct al.

feel t h a t diet should be c o n t i n u e d until a later age, if not indefinitely. TM :~-:;s T h e bulk of the evidence in the published literatm'e suggests t h a t the intellectual level, as such, is not affected if t e r m i n a t i o n of diet takes place after the age of four to six years. W h e r e intensive follow-up information is available, encompassing day-to-day observations as well as r e p e a t e d intelligence tests a n d electroencephalograms, the conclusion is d r a w n t h a t the behavior may deteriorate, learning capacity may deteriorate, but measured level of intelligence does not usually deteriorate?~, 4o T h e serious problem, of course, is obtaining objective criteria on which to base the decision for dietary termination. T h e electroencephalographic findings of our patients have not been illuminating, ~ and elsewhere their value in assessin,,, results of dietary therapy and t e r m i n a t i o n of diet has been questioned. 4x I t is encouraging to note that a n u m b e r of investigators realize that I.Q. and electroencephalograms alone give insufficient evidence for all the complex mental and emotional factors involved.:"'" '"', ~le.~:~ O u r group of 14 phenylketonuric children has m a d e satisfactory progress since termination of diet. W h e r e questions have arisen, emotional stresses could well account for doubtful inental progress. E x a m i n a t i o n of our patients a n d those reported elsewhere indicates that careful follow-up for a i o n g period after termination of diet is needed, as well as continuing r e - e x a m i n a t i o n of criteria for dietary termination. SUMMARY Psychological and biochemical d a t a on 46 phenylketonuric patients ( t 4 treated children, plus one adolescent and one adult, u n t r e a t e d ) have been collected over a period of 7~2 years at the Hospital for Sick Children, Toronto. M e n t a l d e v e l o p m e n t and behavioral anomalies have been e x a m i n e d in the light of biochemical data. T w o definite findings e m e r g e d : (1) W h e r e the diagnosis was e+We wish to acknoMcdgc with thanks the examination of the electroencephalographic t~aclngs on the patients hy Dr. Douglas Met}real o[ the Ncmology staff o[ the Hospital for Sick Children, Toronto.

The .lournal o[ Pediatrics Ms), 1968

m a d e a n d t r e a t m e n t initiated before age two months, the eventual level of intelligence was above the level of m e n t a l deficiency. (2) Even when the m e a s u r e d I.Q. was within n o r m a l limits, there were i n v a r i a b l y mental h a n d i c a p s which resulted in p o o r e r school progress t h a n would be p r e d i c t e d from I.Q. alone. Questions were raised r e g a r d i n g nutritional a d e q u a c y of low p h e n y l a l a n i n e diet, significance of a high incidence of autistic behavior patterns, a n d a c a d e m i c and vocational prognosis of the m o r e intelligent children. F o l l o w - u p was presented of 14 of the above children for periods of 18 to 48 months after t e r m i n a t i o n of diet. T h e children have m a d e satisfactory progress when diet was a r b i t r a r i l y t e r m i n a t e d at age five to eight years. REFERENCES

1. Editorial: Behavior in phenylketonuria, J. A. M. A. 187: 452, 1964. 2. Kleinman, D. S.: Phenylketonuria: A review of some deficits in our information, Pediatrics 33: 123, 1964. 3. Bessman, S. P.: Editorial: Legislation and advances in medical knowledge--acceleration or inhibition, J. PEDrAT. 69: 334, 1966. 4. Partington, M. W.: Observations on phenylketonuria in Ontario, Canad. M. A. J. 84: 985, 1961. 5. Partington, M. W.: Variations in intelligence in phenylketonuria, Canad. M. A. J. 86: 736, 1962. 6. Udenfriend, S., and Cooper, J. R.: Chemical estimation of tyrosine and tyramine, J. Biol. Chem. 196: 227, 1952. 7. Udenfriend, S., and Cooper, J. R.: Assay of L-phenylalanine as phenylethylamine after enzymatic decarboxylation; application to isotopic studies, J. Biol. Chem. 203: 953, 1953. 8. McCaman, M. W., and Robins, E.: Fluorometric method for the determination of phenylalanine in serum, J. Lab. & Clin. Med. 59: 885, 1962. 9. Hackney, I. M.: Autistic behaviour patterns in phenylketonuric children, Canad. Psyehiat. A. J. 12: 333, 1967. 10. Caudle, H. V.: Phenylketonuria without mental retardation, Pediatrics 26: 502, 1960. 11. Coates, S., Norman, A. P., and Woolf, L. I.: Phenylketonuria with normal intelligence and Gowers' muscular dystrophy, Arch. Dis. Child. 32: 313, 1957. t2. Mabry, C., and Podolt, E.: Above average intelligence in untreated phenytketonnrla, J. PEDIAT. 63: 1038, 1963.

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13. Sutherland, B. S., Berry, H. K., and Shlrkey, H. C.: A syndrome of phenylketonuria with normal intelligence and behavior disturbance, J. P~DIAT.57: 521, 1960. 14. Coffelt, R. W.: Unexpected finding from a PKU newborn screening program, Pediatrics 34: 889, 1964. 15. Cabak, V., and Najdanvic, R.: Effect of undernutrition in early life on physical and mental development, Arch. Dis. Child. 40: 532, 1965. 16. Stoch, M. B., and Smythe, P. M.: Does undernutrition during infancy inhibit brain growth and subsequent intellectual development? Arch. Dis. Child. 38: 546, 1963. 17. Cravioto, J.: Application of newer knowledge of nutrition on physical and mental growth and development, Am. J. Pub. Health 53: 1803, 1963. 18. Scrimshaw, N. S., and Behar, M.: Malnutrition in underdeveloped countries, New England J. Med. 272: 137, 1965. 19. Hanley, W. B., Linsao, L., and Davidson, W.: Malnutrition in treated phenylketonuria. In preparation. 20. Homer, F. A., Streamer, C. W., Alejendrino, L. L., Reed, L. H., and Ibbot, F.: The termination of dietary treatment of phenylketonuria, New England J. Med. 266: 79, 1962. 21. Armstrong, M. D., Low, N. L., and Boston, J. F.: Studies on phenylketonuria. IX. Further observations on the effect of phenylalanine-restricted diets on patients with phenylketonuria, Am. J. Clin. Nutr. 5: 543, 1957. 22. Vandeman, P. R.: Termination of dietary treatment for phenylketonuria, Am. J. Dis. Child. 106: 492, 1963. 23. Murphy, D.: Termination of dietary treatment in phenylketonuria, Irish J. M. Sc. 6: 355, 1963. 24. Hudson, F. P.: Results from early treatment of PKU in the north of England, in Holt, K. S., and Milner, J., editors: Neurometabolic disorders in childhood. Proceedings of a symposium held at Sheffield, May, 1963, Edinburgh, 1964, E. and S. Livingstone, Ltd., p. 53. 25. Korey, S. R.: A possible mechanism in phenyl pyruvic oligophrenia, in Etiologic factors in mental retardation. Report of the twenty-third Ross Pediatric Research Conference, Columbus, Ohio, 1957, Ross Laboratories, p. 34. 26. Paine, R. S.: Phenylketonuria, Clin. Proc. Child. Hosp. (Wash.) 20: 143, 1964. 27. Hsia, D. Y.-Y., Knox, W. E., Quinn, K. V., and Paine, R. S.: A one year, controlled study of the effect of low-phenylalanine diet on phenylketonuria, Pediatrics 21: 178, 1958.

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28. Farquhar, J. W., Richmond, J., and Tait, H. P.: Phenylketonuria in pediatric practise, Clin. Pediat. 2: 504, 1963. 29. Moncrieff, A.: When to stop the diet in phenylketonuria, Developmental Med. Child Neurol. 6: 59, 1964. 30. Solomons, G., Kelesbre, L., and Opitz, E.: Evaluation of the effects of terminating the diet in phenylketonuria, J. PEDIAT. 69: 596, 1966. 31. Bickel, H., and Griiter, W.: Dietary treatment of phenylketonuria--experiences during the past nine years, in Bowman, P. W., and Mautner, H. V., editors: Mental retardation: Proceedings of the First International Medical Conference at Portland, Maine, New York, 1960, Grune & Stratton, Inc., p. 272. 32. Bickel, H., and Grfiter, W.: Management of phenylketonuria, in Lyman, F. L., editor: Phenylketonuria, Springfield, Ill., 1963, Charles C Thomas, Publisher, p. 136. 33. Woolfe, L. I., Griffiths, R., Moncrieff, A., Coates, S., and Dillistone, F.: The dietary treatment of phenylketonuria, Arch. Dis. Child. 33: 31, 1958. 34. Koch, R.: Nutrition in the treatment of phenylketonuria, J. Am. Diet. A. 43: 212, 1963. 35. Koch, R.: The clinical team looks at phenylketonuria, in Pediatric aspects of phenylketonuria, U. S. Dept. of Health, Education, and Welfare, Welfare Administration, Children's Bureau, 1964, pp. 8-20. 36. Warner, R.: Personal communication. 37. Fuller, R. M.: Personal communication. 38. Hudson, F. P.: Termination of dietary treatment of phenylketonuria, Arch. Dis. Child. 42: 198, 1967. 39. Langdell, J. I.: Phenylketonuria: Eight year evaluation of treatment, Arch. Gen. Psychiat. 12: 363, 1965. 40. Bruhl, H. H., Arnesen, J. F., and Bruhl, M. G.: Effect of a low-phenylalanine diet on older phenylketonuria patients (Iong range controlled study), Am. J. Ment. Defic. 69: 228, 1964. 41. Fisch, R. O., Sines, L. K., Torres, F., and Anderson, J. A.: Studies on families of phenylketonurics, Am. J. Dis. Child. 109: 427, 1965. 42. Allen, R. J., and Gibson, R. M.: Phenylketonuria with normal intelligence, Am. J. Dis. Child. 102: 115, 1961. 43. Stein, J.: Biochemical aspects of intelligence, in Holt, K. S., and Milner, J., editors: Neurometabolic disorders in childhood--Proceedings of a symposium held at Sheffield, May, 1963, Edinburgh, 1964, E. and S. Livingstone, Ltd., p. 18.